Apamin-sensitive small conductance Ca2+-activated K+ channels (SK channels) are implicated in the molecular and cellular mechanisms underlying learning and memory, and blocking SK channels in vivo affects hippocampal dependent learning tasks. We recently showed that SK2 channels located in the dendritic spines of hippocampal CA1 neurons are functionally coupled to NMDA receptors (NMDAr), forming a Ca2+-mediated feedback loop that affects NMDAr Mg2+ block and synaptic plasticity. It is likely that this regulatory loop underlies the effects of SK channel function on learning and memory. Neurons change their synaptic strength and intrinsic excitability (IE) as a function of previous activity, which is thought to reflect behavioral experience. This ability to modify synaptic strength shapes modern concepts for learning and memory. In Shaffer collateral CA3 to CA1 synapses, long term potentiation (LTP), an activity-dependent increase in synaptic strength, has largely been attributed to increased postsynaptic AMPA-type glutamate receptor activity. However, our new data show that SK2 channels in the spine are also localized within the postsynaptic density of CA1 neurons and are down regulated in a pathway-specific and PKA-dependent manner following induction of LTP. In addition, immunogold EM studies show that the downregulation of SK2 results from a plasticity- and PKA-dependent removal of SK2 channels from the membrane of CA1 spines. Therefore, opposite changes in spine AMPA receptors and SK2 channels act cooperatively to underlie the increased EPSP that represents LTP. We propose that PKA and PP2B form a microdomain signaling complex with SK2 that is coordinated by AKAP and regulates activity-dependent SK2 cycling in the spine. Based upon our previous findings and new unpublished results we have formulated four Specific Aims to test the hypotheses that: 1) Dendritic SK channels are expressed at increasing density with distance from the soma, that they modulate the threshold for induction of synaptic plasticity in a distance-dependent manner, and serve as bi-directional regulators of intrinsic excitability by limiting retrograde b-APs and electrotonic propagation of dendritic EPSPs. 2) LTP decreases spine and dendritic SK2 channel activity in the stimulated pathway, providing a pathway- specific increase in electrotonic propagation of dendritic EPSPs and efficiency of E-S coupling. 3) SK2 channels in the PSD undergo basal recycling through dynamin-dependent endocytosis and recycling endosomes. Upon the induction of LTP recycling is interrupted and the channels enter a population of late endosomes. 4) SK2 channels are components of a macromolecular signaling complex with AKAP79/150 and SAP97 that regulates SK2 channel trafficking. We will test these hypotheses by using an integrated, diverse technical repertoire including immuno electron microscopy, electrophysiology, SK transgenic mice, heterologous co-expression studies, and western and biochemical analysis. PUBLIC HEALTH RELEVANCE: Neurons express a family of calcium-activated potassium channels (SK channels) that are implicated in the molecular and cellular mechanisms underlying learning and memory. Blocking SK channels facilitates learning in animal models of brain damage, and reverses the navigation failure in an animal model associated with the development of cognitive disorders in Alzheimer's disease as well as during normal brain aging. These studies underscore the importance of SK channels in information processing and storage in the brain, and suggest that they are suitable targets for therapeutic intervention in learning deficits associated with trauma, pathology and normal aging.